Laminin receptors and signals in Schwann cells

描述（由申请人提供）：层粘连蛋白对周围神经发育和髓鞘形成很重要。层粘连蛋白突变体在人（先天性肌营养不良，CMD）和小鼠（营养不良，dy）中引起髓鞘形成障碍神经病，其表现为受损的雪旺细胞-轴突相互作用和改变的髓鞘形成。层粘连蛋白在雪旺氏细胞中的作用的分子，以及层粘连蛋白突变体的病理机制在很大程度上仍然未知。我们已经确定了几个层粘连蛋白受体髓鞘形成的雪旺细胞，并表明，他们在周围神经发育的差异表达，这表明他们subserve不同的角色。我们的初步遗传分析证实了这一观点：β 1整合素是出生前建立适当的许旺细胞-轴突关系所必需的，而肌营养不良蛋白聚糖是出生后正常髓鞘形成所必需的。β 1和肌营养不良蛋白聚糖无效的形态表型表明，这些受体通常连接层粘连蛋白的细胞骨架重排在雪旺细胞。这项建议的总体目标是扩大什么是已知的雪旺细胞层粘连蛋白细胞骨架连接的分子基础。 我们已经产生或收集了一组独特的条件等位基因和Cre转基因，这将使我们能够破坏单个或多个已知的主要层粘连蛋白受体在雪旺氏细胞的转基因小鼠。 此外，成像和生化分析β 1整合素空雪旺细胞将阐明β 1如何指导细胞骨架重排。β 1整合素无效的雪旺细胞/神经元外植体的蛋白质组学分析将确定候选的信号分子，连接层粘连蛋白的轴突相互作用所需的细胞骨架的变化。这种综合性的方法将建立不同层粘连蛋白受体在外周神经中的作用，从而阐明CMD和dy突变的发病机制。这些实验产生的信息将共同形成开发CMD和其他遗传性神经病的治疗策略的基础，并促进所有神经病的神经再生和髓鞘再生。

DESCRIPTION (provided by applicant): Laminin is important for peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, CMD) and mouse (dystrophic, dy) that manifests both impaired Schwann cell-axon interactions and altered myelination. The molecules that transduce laminin effects in Schwann cells, and the pathomechanisms of laminin mutants remain largely unknown. We have identified several laminin receptors in myelin-forming Schwann cells and shown that they are differentially expressed across peripheral nerve development, suggesting that they subserve differential roles. Our preliminary genetic analysis confirms this notion: Beta1integrin is required for establishing proper Schwann cell-axon relationships prior to birth, whereas dystroglycan is necessary for normal myelination after birth. The Beta1and dystroglycan-null morphological phenotypes suggest that these receptors normally link laminin to cytoskeletal rearrangements in Schwann cells. The overall goal of this proposal is to expand what is known of the molecular basis of laminin-cytoskeletal linkage in Schwann cells. We have produced or collected an unique group of conditional alleles and Cre transgenes that will allow us to disrupt singly or multiply all known major laminin receptors in Schwann cells of transgenic mice. Furthermore, imaging and biochemical analysis of Beta1integrin-null Schwann cells will elucidate how Beta1 directs cytoskeletal rearrangements. Proteomic analysis of Beta1integrin-null Schwann cell/neuron explants will identify candidate signal molecules that link laminin to the cytoskeletal alterations required for axonal interactions. This comprehensive approach will establish the role of the different laminin receptors in peripheral nerve, thereby clarifying the pathogenesis of CMD and dy mutations. The information produced by these experiments will collectively form a basis for developing treatment strategies of CMD and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies.